We report here the case of a newborn with type 0 SMA. At the first-trimester ultrasonography, an increased NT thickness was detected. After birth, the patient had severe respiratory distress followed by multiple events leading to a fatal outcome.
Currently, the identification of SMA-affected infants prior to the presentation of clinical symptoms is accomplished by newborn screening. However, the severity of this disorder highlights the importance of early prenatal detection.
NT thickness evaluation is associated with multiple foetal malformations, genetic syndromes, intrauterine death risk, congenital heart defects and high risk of miscarriage. Most of the structural anomalies are undetectable prior to childbirth. There are only a few published case reports of an increased NT measurement in association with a diagnosis of SMA in the foetus.
It is well established that an increased NT thickness is a predictive value for an adverse pregnancy outcome, even if conventional karyotyping is normal. The risk of foetal malformations is proportional to the NT thickness. xiii Specifically, if the enlargement is between 3.5 and 4.4 mm, the risk of a foetal chromosome abnormality is 21%, rising to 33% if it is 5 mm, 50% if it is 6 mm, and 65% if it is greater than 6.5 mm. xii However, multiple studies have shown no association between an increased NT thickness and the diagnosis of SMA, suggesting that SMA-affected foetuses have normal NT thickness values. For instance, a study by Zadeh et al. investigated 12 SMA-affected infants with confirmed NT thickness results during pregnancy. All the foetuses had normal NT thickness values ranging from 0.7 to 2.4 mm, implying SMA is not associated with an enlarged NT. Barone and Bianca examining 29 women proposed that foetal genetic testing of the SMN1 gene on the basis of increased NT thickness is not indicated in couples with no previous history of SMA. Nevertheless, the findings of Parra et al. support the idea that SMN2 gene copy number in SMA foetuses is relevant for the development of congenital heart defects and increased NT thickness values.
A broad range of options is needed to help diagnose SMA prenatally. The gold standard for SMA diagnosis is multiplex ligation probe analysis, a targeted test. However, as an increased NT thickness is not currently considered a sign of SMA, this would not have been employed in the case described here. If the signs are not clear, then prenatally the best next-generation sequencing method is exome sequencing; however, it requires specific bioinformatic analysis, as SMN1 and SMN2 are genes with high homology. If a neuromuscular disorder is suspected, then targeted neuromuscular disease panels can be used, as described by Zhao et al. and Tan et al. xviii, In the case described here, more comprehensive diagnostic procedures should have been performed to try and identify the cause of the abnormal NT result prenatally. This information would have given the parents the option of terminating the pregnancy. However, a major consideration in this case was the financial support provided by the parents’ health insurance, which did not allow for extensive diagnostic procedures.
Innovative treatments have been developed for patients with SMA. However, there are currently no treatment options available for patients with type 0 SMA. These patients require respiratory and feeding support, which typically is not enough to keep the patients alive. A recent case report from Matesanz et al. described the clinical course of a patient with type 0 SMA who was treated with nusinersen and onasemnogene abeparvovec. Although the infant had modest motor improvements, she also had continued systemic complications from her SMA, thus highlighting the challenges of treating patients with more severe phenotypes of SMA. Tiberi et al.’s case report presented the case of a type 0 SMA patient with 1 copy of the SMN2 gene. At the age of 13 days, the infant received treatment with nusinersen. Although he showed mild motor improvement, he required a tracheostomy at the age of 4 months. An increasing cardiac and autonomic dysfunction followed and he died at the age of 5 months. xxi Therefore, the available data suggest that despite the development of innovative treatments for SMA, they are unlikely to produce a significant positive effect in type 0 patients.
Although the outcome expectancy of patients with type 0 SMA is pessimistic and the disease leads to early mortality, newborn screening for SMA5q can significantly improve the life expectancy and quality of patients with the other types of SMA. There is evidence that pre-symptomatic treatment initiated as a result of newborn screening improves the outcome of children with genetically proven SMA. Therefore, it is vital to include SMA in the state-funded newborn screening in Latvia in order to initiate treatment pre-symptomatically and obtain the best outcome for patients.